1. Field of the Invention
The invention relates to the fields of chemistry, and biophysics.
2. Description of the Related Art
G-protein coupled receptors (GPCRs) comprise a broad class of membrane-bound proteins that share a variety of structural and functional attributes. See Friedricksson et al. Mol Pharmacol (63)6: p. 1256-1272, 2003; and Friedricksson et al. Mol Pharmacol (67)5: p. 1414-1425, 2005. GPCRs are classified into 1 of 6 classes: A, B, C, D, E, and F, see Friedricksson et al. (2003) and Friedricksson et al. (2005). GPCRs comprise seven transmembrane helical regions, as well as an extracellular portion that binds endogenous ligands.
Extracellular adenosine plays an important role in physiology and initiates most of its effects through the activation of four GPCR subtypes, A1, A2A, A2B and A3 (B. B. Fredholm et al., Annu Rev Pharmacol Toxicol 45, 385 (2005); B. B. Fredholm et al., Pharmacol Rev 53, 527 (2001)). Each of these four receptor subtypes plays an essential role in responding to adenosine in the central nervous system (T. V. Dunwiddie et al., Annu Rev Neurosci 24, 31 (2001); K. A. Jacobson et al., Nat Rev Drug Discov 5, 247 (2006)) regulating pain (J. Sawynok, X. J. Liu, Prog Neurobiol 69, 313 (2003)), cerebral blood flow (Y. Shi et al., J Cereb Blood Flow Metab 28, 111 (2008)), basal ganglia functions (M. A. Schwarzschild et al., Trends Neurosci 29, 647 (2006)), respiration (S. Lahiri et al., Respir Physiol Neurobiol 157, 123 (2007)) and sleep (R. Basheer et al., Prog Neurobiol 73, 379 (2004)). These receptor subtypes are primarily coupled to the cAMP second messenger system and each has its own unique pharmacological profile. The A2A adenosine subtype is linked to Gs and Golf proteins and upon receptor activation, the intracellular levels of cAMP increase. At least three of the four adenosine receptor subtypes (A1, A2A and A2B) are blocked by naturally occurring methylxanthines, such as caffeine, with modest affinity. Interestingly, strong epidemiological evidence suggests that coffee drinkers have a lower risk of Parkinson's disease (M. A. Hernan et al., Ann Neurol 52, 276 (2002)). This effect has been linked to caffeine's interaction with the A2A adenosine receptor, which controls locomotor behavior in basal ganglia together with dopamine D2 and metabotropic glutamate mGluR receptors (S. Ferre, J Neurochem 105, 1067 (2008); S. Ferre et al., Front Biosci 13, 2391 (2008)). Development of more selective compounds for adenosine receptor subtypes could provide a class of therapeutics for treating numerous human maladies, such as pain (J. Sawynok et al., Prog Neurobiol 69, 313 (2003)), Parkinson's disease (M. A. Schwarzschild et al., Trends Neurosci 29, 647 (2006); A. H. Schapira et al., Nat Rev Drug Discov 5, 845 (2006)), Huntington disease (D. Blum et al., S. N. Schiffmann, Lancet Neurol 2, 366 (2003)), asthma (R. A. Brown et al., Br J Pharmacol 153 Suppl 1, S446 (2008)), seizures (M. J. During et al., Ann Neurol 32, 618 (1992)) and many other neurological disorders (D. Blum et al., Lancet Neurol 2, 366 (2003); E. E. Benarroch, Neurology 70, 231 (2008)).